Prognosis of subsequent pregnancies after recurrent spontaneous abortion in first trimester.

The outcome of subsequent pregnancies was studied in 24 women with a history of three or more consecutive spontaneous abortions in the first trimester. Twenty one of the women agreed to forgo active treatment during the study period and three received progestogens or surgical intervention. As the outcome of their first pregnancy after recurrent abortion 18 of the 24 women delivered a liveborn infant after 28 weeks or more. Of all 49 pregnancies in the untreated group during the study, 10 ended in abortion. Only one woman in the study failed to achieve a live birth. Except in exceptional cases encouraging women with recurrent abortion to keep trying for a successful outcome is just as effective as currently recommended treatments.     

Does suppressing luteinising hormone secretion reduce the miscarriage rate? Results of a randomised controlled trial.

OBJECTIVE--To determine whether prepregnancy pituitary suppression of luteinising hormone secretion with a luteinising hormone releasing hormone analogue improves the outcome of pregnancy in ovulatory women with a history of recurrent miscarriage, polycystic ovaries, and hypersecretion of luteinising hormone. DESIGN--Randomised controlled trial. SETTING--Specialist recurrent miscarriage clinic. SUBJECTS--106 women with a history of three or more consecutive first trimester miscarriages, polycystic ovaries, and hypersecretion of luteinising hormone. INTERVENTIONS--Women were randomised before conception to receive pituitary suppression with a luteinising hormone releasing hormone analogue followed by low dose ovulation induction and luteal phase progesterone (group 1) or were allowed to ovulate spontaneously and then given luteal phase progesterone alone or luteal phase placebo alone (group 2). No drugs were prescribed in pregnancy. MAIN OUTCOME MEASURES--Conception and live birth rates over six cycles. RESULTS--Conception rates in the pituitary suppression and luteal phase support groups were 80% (40/50 women) and 82% (46/56) respectively (NS). Live birth rates were 65% (26/40) and 76% (35/46) respectively (NS). In the luteal phase support group there was no difference in the outcome of pregnancy between women given progesterone and those given placebo pessaries. Live birth rates from an intention to treat analysis were 52% (26/50 pregnancies) in the group given pituitary suppression and 63% (35/56) in the controls (NS). CONCLUSIONS--Prepregnancy suppression of high luteinising hormone concentrations in ovulatory women with recurrent miscarriage and hypersecretion of luteinising hormone does not improve the outcome of pregnancy. The outcome of pregnancy without pituitary suppression is excellent.     

One hundred pregnancies after treatment with pulsatile luteinising hormone releasing hormone to induce ovulation.

OBJECTIVE--To review treatment with pulsatile luteinising hormone releasing hormone in infertile women who do not ovulate and are resistant to clomiphene after 100 pregnancies achieved with this treatment. DESIGN--Retrospective analysis of 146 courses of treatment over 434 cycles. SETTING--Infertility clinic. PATIENTS--118 Women whose failure to ovulate was due to idiopathic hypogonadotrophic hypogonadism (n = 39), amenorrhoea related to low weight (n = 17), organic pituitary disease (n = 15), or polycystic ovaries (n = 47). INTERVENTIONS--Dose of 15 micrograms luteinising hormone releasing hormone/pulse subcutaneously every 90 minutes given with a miniaturised pump throughout cycle monitored by ultrasound. Women with hypogonadotrophic hypogonadism had 48 courses, women with amenorrhoea related to low weight 23, women with organic pituitary disease 18, and women with polycystic ovaries 57. END POINT--Follow up of 100 pregnancies achieved in 77 women during six years after introducing treatment. MEASUREMENTS and main results--One hundred pregnancies (seven multiple, 28 miscarriages). Cumulative rates of pregnancy were 93-100% at six months in women with idiopathic hypogonadotrophic hypogonadism, amenorrhoea related to low weight, and organic pituitary disease. In women with polycystic ovaries (cumulative rate of pregnancy 74%) adverse prognostic factors were obesity, hyperandrogenism, and high luteinising hormone concentrations, which were also associated with a high rate of early pregnancy loss. CONCLUSIONS--Treatment with pulsatile luteinising hormone releasing hormone is safe, simple, and effective, and the preferred method of inducing ovulation in appropriately selected patients. Compared with exogenous gonadotrophin treatment there is little need for monitoring, no danger of hyperstimulation, and a low rate of multiple pregnancies.     

Aromatase inhibitors in ovarian stimulation

The selective estrogen receptor modulator, clomiphene citrate (CC), has been the principal drug used for induction of ovulation in women with polycystic ovarian syndrome (PCOS). CC is associated with adverse side effects and low pregnancy rates attributed to long-lasting estrogen receptor depletion. Anastrozole and letrozole are potent, non-steroidal, reversible aromatase inhibitors, developed for postmenopausal breast cancer therapy. We hypothesized that aromatase inhibitors could mimic the action of CC in reducing estrogen negative feedback on follicle stimulating hormone (FSH) secretion, without depleting estrogen receptors. In a series of preliminary studies, we reported the success of aromatase inhibition in inducing ovulation in anovulatory women with PCOS. Moreover, we showed that concomitant use of aromatase inhibitors resulted in a significant reduction of the FSH dose needed for controlled ovarian hyperstimulation. We suggest that aromatase inhibitors act through an increase in endogenous gonadotropin secretion as well as through increased intraovarian androgen levels that may increase ovarian FSH receptors. Recently, we demonstrated the safety of aromatase inhibitors in pregnancy outcome studies examining spontaneous pregnancy loss, multiple pregnancy rates and congenital anomalies compared to a control group of infertility patients treated with CC.     

Dydrogesterone in the reduction of recurrent spontaneous abortion

One hundred and eighty Women with a history of recurrent, unexplained spontaneous abortion (mean 3.5 abortions) were randomised to receive oral dydrogesterone (10 mg b.i.d.), intramuscular human chorionic gonadotrophin (hCG; 5000 IU every 4 days) or no additional treatment (controls). Treatment was started as soon as possible after confirmation of pregnancy and continued until the 12th gestational week. All women received standard supportive care. Abortions were significantly (p ≤ 0.05) less common in the dydrogesterone group (13.4%) than in the control group (29%); there were no statistically significant differences between the hCG group and the control group. There were no differences between the groups with respect to pregnancy complications or congenital abnormalities. In conclusion, hormonal support with dydrogesterone can increase the chances of a successful pregnancy in women with a history of recurrent spontaneous abortion.     

Pregnancy in patients presenting with hyperprolactinaemia.

Ninety-two pregnancies occurred in 76 hyperprolactinaemic patients treated with bromocriptine. Half conceived within three months of attempted conception. There was no evidence of an increased rate of spontaneous abortion, fetal abnormality, or multiple pregnancy; the three twin pregnancies occurred in women who were additionally treated with clomiphene and human chorionic gonadotrophin. Thirty-one patients had radiological evidence of a pituitary tumour; 14 with major radiograph changes in the pituitary fossa or serum prolactin concentrations greater than 100 ng/ml received pituitary irradiation before conception. None of the latter showed evidence of enlargement of the tumour during pregnancy. In contrast two of the four patients with similar tumours but who were not irradiated developed visual field defects, one with gross destruction of the pituitary fossa. Prophylactic treatment to limit subsequent tumour expansion during pregnancy in patients with prolactinomas is indicated, and pituitary irradiation before conception appears to be a safe and effective method to achieve this goal.     

Improvement of in vitro fertilisation after treatment with buserelin,an agonist of luteinising hormone releasing hormone

Treatment with buserelin, an agonist of luteinising hormone releasing hormone, and human menopausal gonadotrophin was compared with the conventional treatment of clomiphene citrate and human menopausal gonadotrophin in the outcome of in vitro fertilisation. Seventy seven infertile women had 83 cycles of treatment with buserelin and human menopausal gonadotrophin, and concurrently another 328 infertile women were treated with clomiphene citrate and human menopausal gonadotrophin. Seven (8%) cycles were cancelled owing to inadequate superovulation or ovarian hyperstimulation in the women receiving buserelin and 103 (31%) were cancelled because of poor follicular development in those receiving clomiphene citrate. The mean number of oocytes recovered was significantly higher with buserelin (9·5 (SD 4·5) v 5·5 (2·2)) as was the mean number of embryos obtained (4·3 (2·4) v 2·9 (1·7)). Significantly more women who had an embryo transfer became clinically pregnant after treatment with buserelin (53% (30/57) v 30% (48/159), or 36% v 14% of treatment cycles). Altogether 33% (10) of pregnancies in women treated with buserelin were multiple compared with 23% (11) in those treated conventionally. Of the 17 completed pregnancies in women treated with buserelin, 11 resulted in the birth of live babies (eight singletons, two sets of twins, and one set of triplets) and six failed, five before 12 weeks'' gestation and one at 22 weeks. The 13 continuing pregnancies (32 weeks) were eight singletons, two sets of twins, and three sets of triplets. Of the 48 completed pregnancies in women treated with clomiphene citrate, 35 resulted in the birth of live babies (26 singletons, five sets of twins and four sets of triplets) and 13 failed, eleven before 12 weeks'' gestation and two by 27 weeks.Buserelin increased the chance of pregnancy after in vitro fertilisation compared with conventional treatment, but the risk of multiple pregnancy may be increased.     

Epigenetic status of imprinted genes in placenta during recurrent pregnancy loss

An analysis of differential methylation of 47 imprinted genes in placenta tissues of spontaneous abortions at the first trimester of pregnancy from women with recurrent pregnancy loss or with one sporadic abortion was performed using the DNA-microarray approach. We showed that epimutations of the imprinted genes were registered significantly more often in abortions from women with recurrent miscarriage in contrast to the embryos from women with sporadic pregnancy loss with frequency of 6.2 and 3.7% per locus, respectively (p < 0.01). The predominant type of epimutation appeared to be a postzygotic hypomethylation of the imprinted genes on chromosomes of maternal origin, which was observed in the examined samples in 5.1 and 2.89% of cases, respectively. Replicative study of the methylation status of seven imprinted genes (DLK1, PEG10, PLAGL1, KCNQ1OT1, PEG3, GRB10, and PEG1/MEST) in the enlarged embryo samples supported the results of microarray analysis in respect to both epimutation frequency and predominance of somatic hypomethylation of maternal alleles. It was also demonstrated that pregnancy loss was associated with multilocus methylation defects of imprinted genes, the frequency of which was also significantly increased in the placental tissues of spontaneous abortions in women with recurrent miscarriage.     

Investigation and treatment of amenorrhoea resulting in normal fertility.

A simple scheme of investigation and treatment to restore fertility in amenorrhoeic women is described. Fifty-nine patients with amenorrhoea not due to primary ovarian failure were treated variously as appropriate, mainly with clomiphene (25), bromocriptine (15), or human menopausal gonadotrophins (12), and six by diet to increase their weight. All ovulated, and by the end of the study 55 (93%) had conceived, 42 (71%) had delivered at least one surviving child, and five others (8%) were pregnant and awaiting delivery. Conception rates were 49% within two cycles of treatment and 66% within three cycles; using life-table method to standardise the cumulative conception rates by correcting for patients who did not continue as long as others in the study, the expected conception rate was 79% in six cycles, 94% in 12 cycles, and 98% after 16 cycles. The multiple pregnancy rate was 13% and abortion rate 22%. Delivery rate (for a viable baby) were 48% within 11 months of starting treatment and 53% within one year; expected rates were 76% in 18 months and 97% in two years. The results show that a relatively simple scheme of classifying amenorrhoeic disorders endocrinologically followed by treatment directed at inducing ovulation allows amenorrhoeic women without primary ovarian failure to achieve conception and delivery rates equal to those in normal women.     

Maternal Th1- and Th2-type reactivity to placental antigens in normal human pregnancy and unexplained recurrent spontaneous abortions.

Spontaneous abortion is the most common complication of pregnancy, but the etiology of a significant proportion of abortions is still unknown. We have examined the production of Th1- and Th2-type cytokines by women with unexplained recurrent spontaneous abortion (RSA) since it appears that successful murine pregnancy occurs in a Th2-dominant situation and that Th1-type immunity is associated with pregnancy failure. We have compared maternal reactivity toward placental antigens in women with a history of successful pregnancy with that in women with a history of RSA. This was done by coculturing maternal peripheral blood mononuclear cells (PBMC) with autologous placental cells and also by stimulating maternal PBMC with antigens from a choriocarcinoma cell line of trophoblastic origin. We detected significantly greater levels of the Th2 cytokines IL-6 and IL-10 in normal pregnancy compared to unexplained RSA and significantly higher levels of the Th1 cytokine IFN-gamma in RSA compared to normal pregnancy. These results suggest that women with normal pregnancy have a higher Th2 bias, while women with a history of RSA evince a bias toward Th1-type reactivity.     

Case report: a most peculiar family with spontaneous, recurrent ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) mostly occurs as a complication of induction of ovulation. However, rarely, it may occur spontaneously at the beginning of a natural pregnancy and in the absence of any assisted reproductive treatment. Spontaneous OHSS has been reported in pregnant women affected by hypothyroidism, polycystic ovary syndrome, gonadotropin-producing pituitary adenoma, but also in normal pregnancies. The aetiology of this condition is still unclear. We hereby report on a case of spontaneous, familial, recurrent OHSS in a 26-year-old primipara whose first-degree cousin, paternal grandmother and a number of other members of her father's family had suffered from a similar condition. This case seems to support the concept of a genetic predisposition for spontaneous OHSS thereby suggesting the need for preventive and therapeutic strategies.     

阴道超声在药物诱导排卵监测中的临床应用价值

目的：探讨阴道超声监测卵泡发育对排卵障碍不孕症患者的临床应用价值。方法：45例不孕症患者中18例用氯米芬促排卵,14例用尿促性素促排卵,13例用氯米芬和尿促性素序贯应用促排卵,患者于月经第9天起阴道超声监测卵泡发育和子宫内膜厚度,并根据监测结果调整药物剂量,诱发排卵指导同房,排卵后2周进行妊娠随访,随访至妊娠3个月。结果：45例患者子宫附件均正常者33例,多囊卵巢7例,子宫肌瘤4例,附件混合性包块1例。45例患者卵泡发育成熟并排卵31例,排卵率为68．9％,小卵泡排卵2例,卵泡不发育6例,未破裂卵泡黄素化综合征4例,卵巢过度刺激综合征2例。生化妊娠1例,临床妊娠9例,临床妊娠率为29．0％,其中1例于停经45天时自然流产。结论：经阴道超声监测卵泡发育和排卵准确、直观,对不孕症病因的诊断和指导治疗均有重要作用。     

Trial of support treatment with human chorionic gonadotrophin in the luteal phase after treatment with buserelin and human menopausal gonadotrophin in women taking part in an in vitro fertilisation programme.

OBJECTIVE--To evaluate the effect of support with human chorionic gonadotrophin in the luteal phase in women taking part in an in vitro fertilisation programme after buserelin and human menopausal gonadotrophin were used to hyperstimulate their ovaries. DESIGN--Controlled group comparison. SETTING--Outpatient department of a private hospital. PATIENTS--115 Women with indications for in vitro fertilisation, all of whom had at least one embryo transferred. INTERVENTIONS--After suppression of the pituitary with buserelin the ovaries of all the women were stimulated with human menopausal gonadotrophin on day 4 of the luteal phase. Human chorionic gonadotrophin (10,000 IU) was given to induce ovulation, and oocytes were recovered 34 hours later. Embryos were transferred 46 to 48 hours after insemination. Women who had received the 10,000 IU of human chorionic gonadotrophin on a date that was an uneven number (n = 61) were allocated to receive support doses of 2500 IU human chorionic gonadotrophin three and six days after that date. The remaining 54 women did not receive hormonal support. END POINT--Determination of the rates of pregnancy. MEASUREMENTS and main results--Support with human chorionic gonadotrophin did not significantly alter the progesterone or oestradiol concentrations in the early or mid-luteal phase. The mean (range) progesterone concentrations in the late luteal phase in women who did not become pregnant were, however, significantly higher in those who received support (16(9-110) nmol/l nu 8(4-46) nmol/l), and the luteal phase was significantly longer in this group (14 days nu 12 days). The rate of pregnancy was significantly higher in the women who received support than in those who did not (25/61 nu 8/54). CONCLUSIONS--When buserelin and human menopausal gonadotrophin are used to hyperstimulate ovaries support with human chorionic gonadotrophin in the luteal phase has a beneficial effect on in vitro fertilisation.     

Serum inhibin as an index of ovarian function in women undergoing pituitary suppression and ovarian stimulation in an in vitro fertilization program.

Serum inhibin concentrations, determined by radioimmunoassay, were measured in women undergoing pituitary suppression with buserelin and subsequently ovarian stimulation with human menopausal gonadotropin (hMG). Three types of treatment cycle were investigated, namely (1) cycles showing a normal ovarian response and resulting in a pregnancy; (2) cycles showing a poor response to the hMG, and (3) cycles previously showing a poor ovarian response but augmented with biosynthetic human growth hormone. Good correlations were seen between serum inhibin concentrations and serum progesterone in the luteal phase prior to buserelin (Rs = 0.68), serum oestradiol on the 8th day of hMG administration (Rs = 0.82) or the day of ovulatory trigger (Rs = 0.78), and the number of follicles greater than or equal to 14 mm on the day of ovulatory trigger (Rs = 0.71). These results show inhibin to be a good index of ovarian function in women exhibiting a range of ovarian responses to stimulation in an in vitro fertilization program.     

Influence of past reproductive performance on risk of spontaneous abortion.

OBJECTIVE--To investigate the incidence of spontaneous abortion in a population of women in order to establish their risk of spontaneous abortion and the obstetric factors predisposing to it. DESIGN--Prospective study of women recruited by radio and poster appeal and from hospital outpatient clinics. SETTING--English provincial community. PATIENTS--630 Women from the general population intending to become pregnant. INTERVENTIONS--The viability of the pregnancy was assessed by abdominal ultrasonography before completion of the eighth week, and the assessment was repeated if vaginal bleeding occurred. MAIN OUTCOME MEASURE--Spontaneous abortion or live births in women with or without a previous history of spontaneous abortion. RESULTS--The overall incidence of clinically recognisable spontaneous abortion before 20 weeks of gestation was 12% (50/407 pregnancies). The risk of spontaneous abortion in each category of patient was classified with respect to the patient''s past reproductive performance and found to be influenced greatly by her previous obstetric history. In primigravidas and women with a history of consistently successful pregnancies the incidences of abortion were low (5% (4/87) and 4% (3/73) respectively), whereas women with only unsuccessful histories had a much greater risk of aborting the study pregnancy (24% (24/98)), even when their sole pregnancy had ended in abortion (20% (12/59)). The outcome of the last pregnancy also influenced the outcome of the study pregnancy; only 5% of women (5/95) whose previous pregnancy had been successful aborted, whereas the incidence of loss of pregnancy among women whose last pregnancy had aborted was 19% (40/214). CONCLUSIONS--A knowledge of the patient''s reproductive history is essential for the clinical assessment of her risk of spontaneous abortion. As the most important predictive factor for spontaneous abortion is a previous abortion, the outcome of a woman''s first pregnancy has profound consequences for all subsequent pregnancies.     

Effects of legal termination on subsequent pregnancy.

Two hundred and eleven patients who had undergone vaginal termination and were pregnant again were investigated; 43-2% had become pregnant within one year of termination. The overall fetal loss in the 211 patients was 17-5% compared with 7-5% in a group matched for parity but consisting of patients who were pregnant after a spontaneous abortion. Altogether 4-3% of pregnancies after legal abortion ended as first trimester abortions, 8-5% as second trimester abortions, and 13-7% in premature delivery. Among 11 women whose cervices had been lacerated at the time of legal termination the fetal loss in subsequent pregnancy was 45-5%, and only one pregnancy went beyond 36 weeks. Routine Shirodkar suture may be beneficial when the cervix is known to have been damaged at legal abortion. Several patients had asked that their general practitioner should not be told of their termination, and such patients may not admit their termination during a subsequent pregnancy, which could thus be jeopardised. No evidence was found to suggest that infants of patients with a history of legal termination are small for dates.     

Induction of Ovulation

Every effort should be made to find the cause of anovulation since specific therapy directed at correction of a specific hormonal deficiency or excess is, of course, much more effective than any empiric treatment. Moreover, some patients with disorders of ovulation may have serious, even fatal, underlying disorders. The use of thyroid or cortisone has been disappointing except in the treatment of an overt deficiency of thyroid or cortisone or an excess of adrenal androgens. Estrogens and progestational agents have not been consistently effective in the induction of ovulation. The use of clomiphene citrate, which apparently stimulates the release of gonadotropins, and the use of purified gonadotropins of human origin have been quite successful in the induction of ovulation in a variety of disorders of ovarian function. Because of real and potential hazards, the use of these new agents should be restricted to women for whom pregnancy is the primary goal or in whom standard methods of therapy have failed. Neither drug has been released by the Food and Drug Administration for routine clinical use.     

Ovulating induction methods in rabbit does: the pituitary and ovarian responses

The aim of this study was to compare the pituitary and ovarian responses in rabbit does subjected to different methods of ovulation induction. Forty-eight receptive females were randomly distributed into six groups (N = 8) and were inseminated with standard glass catheters. Buserelin intramuscular (BM) does were inseminated using a pool of fresh heterospermic semen and an intramuscular injection of 1 μg of buserelin acetate to induce ovulation. Buserelin intravaginal (BV) does were inseminated in a similar way, but ovulation was induced with the GnRH analogue (10 μg of buserelin acetate) combined with 0.5 mL of semen extender. The raw semen (R) and saline groups (S) were inseminated with undiluted semen or saline, respectively, without any inducer of ovulation. Another group (A) received lumbar anaesthesia (1.5 mL of 2% lidocaine), and only the empty catheter was introduced into the vagina. The AR does were treated the same way as group A but were inseminated with raw semen instead of an empty catheter. Blood samples were collected to determine the LH concentrations before and after AI (30, 60, 90, and 120 minutes). Ovulation, pregnancy, and conception rates were determined after euthanasia on day 14 post AI. Ovulating does had higher mean LH concentrations than nonovulating does (197.9 vs. 45.9 ng/mL; P < 0.05). The ovulation rates of buserelin intramuscular and intravaginal does were 100%, and the pregnancy rates were 87.5% and 100%, respectively. Rabbit does in groups A and AR did not ovulate and had similar mean plasma LH concentrations after 60 minutes compared with the S group (49.4 and 49.2 ng/mL vs. 41.6 ng/mL, respectively), which reached ovulation and pregnancy rates of 37.5%. Does inseminated only with raw semen had an ovulation rate of 75% and a pregnancy rate of 62.5%; they also demonstrated higher plasma LH concentrations than does of the S, A, and AR groups. In conclusion, ovulation in rabbit does can be induced by exogenous GnRH administration (im and intravaginal). The high plasma LH concentration and ovulation rate in the R group with respect to the S and A groups could weakly indicate the presence of some molecules in the seminal plasma that could act on or be absorbed by vaginal mucosa. Sensory stimulation and “seminal factors” probably exert a synergy on the ovulation response as demonstrated by the comparison of LH release and the ovulation response in the R, S, RA, and A groups.     

Abortion-seeking behaviour among Nigerian women

This study used data from a community-based survey to examine women's experiences of abortion in Nigeria. Fourteen percent of respondents reported that they had ever tried to terminate a pregnancy, and 10% had obtained an abortion. The majority of women who sought an abortion did so early in the pregnancy. Forty-two percent of women who obtained an abortion used the services of a non-professional provider, a quarter experienced complications and 9% sought treatment for complications from their abortions. Roughly half of the women who obtained an abortion used a method other than D&C or MVA. The abortion prevalence and conditions under which women sought abortions varied by women's socio-demographic characteristics. Because abortion is illegal in Nigeria except to save the woman's life, many women take significant risks to terminate unwanted pregnancies. Reducing the incidence of unwanted pregnancy and unsafe abortion can significantly impact the reproductive health of women in Nigeria.